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The Use of Diethylstilbestrol in Threatened Abortion
THE UD OF DIE'l'HYLSTILUS'l'BOL IN 'l'HUAT:.UED AiWI.flON DAVID RoBINSON, M.D.,• AND LANDRUM
B.
SHETTLEs, M.D., NEw YoRK,
N.Y.
(From the Department of Obstetrics and Gynecology of the College of Physicians and Surgeons, Columbia University, and the Sloane Hospital, Columbia-Presbyterian Medical Center)
therapy of threatened abortion has for many years consisted primarily T HE of bed rest and sedation. With the advent of vitamins and hormone products, it was inevitable that these substances would be utilized in the problem of threatened abortion. Progesterone in particular had good theoretical indication. Corner and Allen 1 showed it was essential for the conservation of early pregnancy, and Reynolds and All€n 2 proved its ability to inhibit ut€rine contractility in the rabbit. Yet, the early results with progesterone were inconclusive, possibly because the dosage used was too low from a physiologic standpoint. The possible importance of progesterone was re-emphasized when Guterman and Tulsky 3 showed that 97 per cent of the patients with low pregnandiol excretion aborted, with or without treatment. On the other hand, when pregnandiol excretion was normal, 80 per cent did not abort. Guterman concluded the dosage of 1 to 25 mg. daily at first used by him was too low, and recommended a daily intramuscular dose of 80 to 120 mg. of progesterone. The synthetic estrogen, diethylstilbestrol, has more recently become a popular form of therapy in threatened abortion. The public has been so frequently told of the virtue of this drug through articles appearing in lay journals that it now requires a courageous physician to refuse this medication. The mass of pharmaceutical literature, extolling the wonders of this drug, has also rendered most practitioners amenable to his patient's demands. This situation, together with the understandable desire to do something positive toward rescuing a teetering pregnancy, has resulted in the widespread use of diethylstilbestrol in threatened abortion. The two most influential papers in the medical literature giving impetus to the use of diethylstilbestrol have been written by Karnaky 4 and Smith. 5 Karnaky's original paper on this subject appeared in 1942. At that time, he !'itated that threatened abortion was best treated with the continuous use of diethylstilbestrol until the eighth month of pregnancy. Immediate treatment consisted of the injection of 25 mg. of diethylstilbestrol into the anterior wall of the cervix, followed by 25 mg. of the drug by mouth every fifteen minutes until all pain ceased. This was followed by 10 mg. every hour for six doses, then 5 mg. every hour for six doses, and then 10 mg. each night until the eighth month. By this technique, only 5 of 19 cases aborted. No precise definition of threatened abortion was stated and no controls were used. In a more recent paper, Karnaky 6 has increased the amount of diethylstilbestrol employed. One hundred mg. are given orally every fifteen minutes until cramps and spotting cease. Then, 25 mg. three times daily are given for a •Present address, 99 Pratt Street, Hartford, Conn.
1330
Volume 63 Number 6
USE OF DIETHYLSTILBESTROL
:m THREATENED
ABORTION
1331
week, followed by a maintenance dose of 25 mg. daily until the eighth month. The histories of 21 patients are briefly reported with a fetal salvage rate of 76 per cent. Smith's paper on this subject appeared in 1948. Her series consisted of 219 cases treated with diethylstilbestrol. Of these, 72 per cent had living children, and 78 per cent carried to the twenty-eighth week. These figures were compared favorably with Hertig's estimated spontaneous cure rate of 50 per cent. Simultaneous control studies were not carried out. All these patients exhibited vaginal bleeding beyond the date of implantation bleeding. Other papers 7 have appeared attesting the efficiency of diethylstilbestrol in threatened abortion. However, in a well-controlled study, Crowder, Bills, and Broadbent,8 using massive diethylstilbestrol dosage, were unable to prove the value of this drug as a panacea. With a series of 100 cases, they reported a 51 per cent salvage rate in the diethylstilbestrol-treated cases, as compared with a 57 per cent rate in controls treated by bed rest and sedation.
Materials and Methods Early in 1948, a carefully controlled study of threatened abortion was begun at the Sloane Hospital for Women. The criteria for a threatened abortion were established to include cases of vaginal bleeding after a missed period, with or without abdominal cramps. Cases of bleeding from the cervix itself, and cases with dilatation or effacement of the cervix were excluded after gentle and bimanual examination. The cases selected were placed alternately in either an "A" or "B" series. The "A" series was treated by diethylstilbestrol while the "B" series served as a control, without specific therapy. All patients were hospitalized and kept on bed rest until bleeding had ceased for 24 hours. The "B" series was allowed analgesics and sedation such as phenobarbital, 30 mg. three times daily. The "A" series was given diethylstilbestrol orally as recommended by Smith 5 in a progressive dosage schedule, receiving a maximum of 125 mg. daily at the thirty-fifth week. The patients were also allowed analgesics and sedatives. Progesterone, vitamin E, and thyroid were not used as accessory medications. A total of 112 patients was admitted for study. Fifty-seven were originally assigned to series "A,'' and 55. to series "B." However, it 1 was necessary to delete 6 cases from series 1 1 A,'' and 13 cases from series ' B.'' The six patients in the "A" series were excluded because 3 were not pregnant, two had no follow-up, and 1 aborted before therapy could be institute?. The 13 exclusions in series '' B'' were carried out because 5 cases were ectopic pregnancies, 2 had no follow-up, 2 were hydatid moles, 3 were completed abortions, and 1 was not pregnant. There remained 51 stilbestrol-treated eases ("A" series), and 42 control eases (' 'B'' series). Salvage studies (Table I) reveal that 11 of 51 "A" cases delivered viable infants (21 per cent), and 16 of the 42 "B" cases delivered viable infants (38 per cent). TABLE
I.
COMPARISON OF FINAL RESULTS OF DIETHYLSTILBESTROL-TREATED AND CoNTROL SERIES
SERIES
B
42
16
38
Careful survey of the individual eases suggest that the two series were, so far as could be determined, comparable. In series "A," 3 patients aborted within 24 hours of the beginning of treatment, and, in series "B," 7 aborted
ROBINSON AND
1332
SHJ
.\m. J, Ob,t. & Gynec June, IQ~~
in the same period of time. In series ''A,'' there were 4 cases of fibroids. Three of these patients aborted. In series "B," there were three cases of fihroids. Two of these patients aborted. There were three cases of placenta previa, all occurring in the "B" series. Two of these pregnancies terminated with living infants. No cases of toxemia developed in either series. The salvage rate was higher in both series when bleeding was unaccompanied by cramps (Tables II and III), the salvage rate in series "A" rising to 36 per cent, and in series "B" to 58 per cent. TABLE
II.
TABLB
RESULTS IN PATIENTS HAVING BLEEDING WITHOI'T CRAMPS
ITI.
RESULTS IN PA'fiENTS HAVI:-iG RD;BDINil Wi1'1! CRAMPS ~~~==~=r========~
SERIES
A-(;c;D'C7ie-;-t.--hy"ls-,-til"'b-estrcif)
7
R (Controls)
I
NO. OF CASES
I
---------37-----·~
....
VIABLE INFANTS DELIVERED
PER CENT SALVAGED
7 9
19 30
BO
These results give no evidence of a favorable therapeutic effect from diethylstilbestrol in threatened abortion. Total results, the salvage of 27 of 93 cases, or 29 per cent, do not compare favorably with other reported figures. Hertig and Livingstone, 9 for example, estimated that 20 per cent of all pregnancies threatened to abort with a 50 per cent spontaneous salvage. Parish10 reported a 57 per cent salvage. Colvin and collaborators 11 reported a 70 per cent salvage rate. Rutherford,l 2 however, reported only 24 of 91 threatened abortions carried to term. A possible explanation of our low figure is that all of these were clinic patients who are not likely to report bleeding and cramps as early as the patients seen in private practice.
Comment Various theories have been propounded as to why diethylstilbestrol should be a logical agent in the treatment of threatened abortion. The most widespread theory is that promulgated by the Smiths. 13 They believe that effective action is due to diethylstilbestrol acting like estrogenic oxidation products in causing an increased utilization of chorionic gonadotropin, which, in turn, produces an increased output of progesterone. An adequate production of progesterone is essential for the preservation of pregnancy. Heckel and Allen14 had shown that, in the pregnant rabbit, estrogen administration had maintained progesterone secretion and delayed delivery. The Smiths demonstrated increased pregnandiol excretion following diethylstilbestrol therapy. The Smiths' contention that diethylstilbestrol caused increased progesterone formation as evidenced by increased pregnandiol excretion in the urine has been contested by Davis and Fugo. 16 Hanley 17 was also unable to show increased p1'ogesterone production with diethylstilbestrol treatment in pregnancy. Notwithstanding the questionable modus operandi of diethylstilbestrol in threatened abortion, the high salvage rate in Smith's series (72 per cent) is an excellent attainment, and might be regarded as evidence for the use of diethylstilbestrol on purely empirical grounds. However, Colvin, Bartholomew, Grimes, and Fish 11 reported on 1,570 cases of threatened abortion
Volume 63 Number 6
USE OF DIETHYLSTILBES'rROL IN THREATENED ABORTION
1333
treated conservatively without hormones. Seventy per cent resulted in term babies, 2 per cent in premature deliveries, and 28 per cent aborted. These salvage figures compare favorably with those of Karnaky and Smith. Threatened abortion is not a single disease entity. It is an expression of multiple etiological agents. It is well known that a majority of abortions are due to defective ova. Hertig and Uvingstone, 9 in a study of 1,000 abortions, found 62 per cent were due to abnormal ova. Colvin and associates 11 found 86 per cent of their series aborted because of defective ova. Hertig and Rock 18 have shown that defects in the ovum are apparent even before the first missed menstrual period and thus are not amenable to therapy. The maternal factors in threatened abortion usually listed in the obstetrical textbooks include acute febrile illnesses, surgery, accompanied by sepsis and shock, x-ray therapy, trauma, anesthesia, nutritional deficiencies such as deficiencies of vitamins E. K, and C, endocrine deficiencies such as that of progesterone and thyroid, and anatomical abnormalities. The latter included submucous fibroids, endometrial polyps, previous amputation of the cervix, a septate uterus, and adherent retroversion. Jones and Delfs19 have shown, in studying threatened abortions, that such factors as deficient progesterone production, lowered thyroid .secretion, vitamin E deficiency, uterine abnormalities, and ovular abnormalities may play a role in the abortion. It is obvious that any of these factors might play a role in an individual case of threatened abortion. To expect, on theoretical grounds, that diethylstilbestrol should remedy all these factors appears inconceivable. The present study indicates that diethylstilbestrol is, in fact, a dismal failure in the general treatment of threatened abortion.
Conclusions 1. In a careful comparison of 51 diethylstilbestrol-treated threatened abortions with a control series of 42 untreated cases, there was no evidence that diethylstilbestrol increased the pregnancy salvage rate. 2. On account of the multiplicity of the causes leading to threatened abortion, it is hardly conceivable that one substance could serve as a panacea. 'rhe authors desire to express their grateful appreciation of the helpful suggestions and criticisms given this project by Dr. Howard C. Taylor, Jr.
References 1. 2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Corner, G. W., and Allen, W. M.: Am. J. Physiol. 88: 326, 1929. Reynolds, S. R., and Allen, W. M.: Am. J. Physiol. 102: 3, 1932. Guterman, H. S., and Tulsky, A. G.: AM. J. OBST. & GYNEC. 58: 495, 1949. Karnaky, K. J.: South. M. J. 35: 838, 1942. Smith, 0. W.: AM. J. OBST. & GYNEC. 56: 821, 1948. Karnaky, K. J.: Arizona Med. 8: 36, 1951. (a) Rosenblum, G., and Melinkoff, E.: West. J. Surg. 55: 597, 1947. (b) Ross, J. W.: .J. Nat. M.A. 43: 20, 1951. Crowder, R. E., Bills, E. S., and Broadbent, J. S.: AM. J. OBST. & GYNEC. 60: 896, 1950. Hertig, A. T., and Livingstone, R. C.: New England J. Med. 230: 797, 1944. Parish, T. N.: J. Obst. & Gynaec. Brit. Emp. 42: 1107, 1935. Colvin, E. D., Bartholomew, R. A., Grimes, W. H., and Fish, J.: AM. J. OBST. & GYNEC. 59: 1208, 1950. Rutherford, R.N.: Surg., Gynec. & Obst. 74: 1139, 1942. Smith, 0. W., Smith, G. W., and Schiller, S.: J. Clin. Endocrinol. 1: p. 461, 1941. Heckel, G. P., and Allen, W. M.: Endocrinology 24: 137, 1939. Smith, 0. W., and Smith, G. W.: Proc. Soc. Exper. Bioi. & Med. 57: 198, 1944. Davis, M. E., and Fugo, N. W.: Proc. Soc. Exper. Bioi. & Med. 65: 283, 1947. Hanley, B. J.: Discussion of paper by Colvin, Bartholomew, Grimes, and Fish.n Rock, J., and Hertig, A. T.: AM. J. OBST. & GYNEC. 55: 6, 1948. Jones, G. E. S., and Delfs, E.: J. A.M. A. 146: 1212, 1951.
B.
SHETTLEs, M.D., NEw YoRK,
N.Y.
(From the Department of Obstetrics and Gynecology of the College of Physicians and Surgeons, Columbia University, and the Sloane Hospital, Columbia-Presbyterian Medical Center)
therapy of threatened abortion has for many years consisted primarily T HE of bed rest and sedation. With the advent of vitamins and hormone products, it was inevitable that these substances would be utilized in the problem of threatened abortion. Progesterone in particular had good theoretical indication. Corner and Allen 1 showed it was essential for the conservation of early pregnancy, and Reynolds and All€n 2 proved its ability to inhibit ut€rine contractility in the rabbit. Yet, the early results with progesterone were inconclusive, possibly because the dosage used was too low from a physiologic standpoint. The possible importance of progesterone was re-emphasized when Guterman and Tulsky 3 showed that 97 per cent of the patients with low pregnandiol excretion aborted, with or without treatment. On the other hand, when pregnandiol excretion was normal, 80 per cent did not abort. Guterman concluded the dosage of 1 to 25 mg. daily at first used by him was too low, and recommended a daily intramuscular dose of 80 to 120 mg. of progesterone. The synthetic estrogen, diethylstilbestrol, has more recently become a popular form of therapy in threatened abortion. The public has been so frequently told of the virtue of this drug through articles appearing in lay journals that it now requires a courageous physician to refuse this medication. The mass of pharmaceutical literature, extolling the wonders of this drug, has also rendered most practitioners amenable to his patient's demands. This situation, together with the understandable desire to do something positive toward rescuing a teetering pregnancy, has resulted in the widespread use of diethylstilbestrol in threatened abortion. The two most influential papers in the medical literature giving impetus to the use of diethylstilbestrol have been written by Karnaky 4 and Smith. 5 Karnaky's original paper on this subject appeared in 1942. At that time, he !'itated that threatened abortion was best treated with the continuous use of diethylstilbestrol until the eighth month of pregnancy. Immediate treatment consisted of the injection of 25 mg. of diethylstilbestrol into the anterior wall of the cervix, followed by 25 mg. of the drug by mouth every fifteen minutes until all pain ceased. This was followed by 10 mg. every hour for six doses, then 5 mg. every hour for six doses, and then 10 mg. each night until the eighth month. By this technique, only 5 of 19 cases aborted. No precise definition of threatened abortion was stated and no controls were used. In a more recent paper, Karnaky 6 has increased the amount of diethylstilbestrol employed. One hundred mg. are given orally every fifteen minutes until cramps and spotting cease. Then, 25 mg. three times daily are given for a •Present address, 99 Pratt Street, Hartford, Conn.
1330
Volume 63 Number 6
USE OF DIETHYLSTILBESTROL
:m THREATENED
ABORTION
1331
week, followed by a maintenance dose of 25 mg. daily until the eighth month. The histories of 21 patients are briefly reported with a fetal salvage rate of 76 per cent. Smith's paper on this subject appeared in 1948. Her series consisted of 219 cases treated with diethylstilbestrol. Of these, 72 per cent had living children, and 78 per cent carried to the twenty-eighth week. These figures were compared favorably with Hertig's estimated spontaneous cure rate of 50 per cent. Simultaneous control studies were not carried out. All these patients exhibited vaginal bleeding beyond the date of implantation bleeding. Other papers 7 have appeared attesting the efficiency of diethylstilbestrol in threatened abortion. However, in a well-controlled study, Crowder, Bills, and Broadbent,8 using massive diethylstilbestrol dosage, were unable to prove the value of this drug as a panacea. With a series of 100 cases, they reported a 51 per cent salvage rate in the diethylstilbestrol-treated cases, as compared with a 57 per cent rate in controls treated by bed rest and sedation.
Materials and Methods Early in 1948, a carefully controlled study of threatened abortion was begun at the Sloane Hospital for Women. The criteria for a threatened abortion were established to include cases of vaginal bleeding after a missed period, with or without abdominal cramps. Cases of bleeding from the cervix itself, and cases with dilatation or effacement of the cervix were excluded after gentle and bimanual examination. The cases selected were placed alternately in either an "A" or "B" series. The "A" series was treated by diethylstilbestrol while the "B" series served as a control, without specific therapy. All patients were hospitalized and kept on bed rest until bleeding had ceased for 24 hours. The "B" series was allowed analgesics and sedation such as phenobarbital, 30 mg. three times daily. The "A" series was given diethylstilbestrol orally as recommended by Smith 5 in a progressive dosage schedule, receiving a maximum of 125 mg. daily at the thirty-fifth week. The patients were also allowed analgesics and sedatives. Progesterone, vitamin E, and thyroid were not used as accessory medications. A total of 112 patients was admitted for study. Fifty-seven were originally assigned to series "A,'' and 55. to series "B." However, it 1 was necessary to delete 6 cases from series 1 1 A,'' and 13 cases from series ' B.'' The six patients in the "A" series were excluded because 3 were not pregnant, two had no follow-up, and 1 aborted before therapy could be institute?. The 13 exclusions in series '' B'' were carried out because 5 cases were ectopic pregnancies, 2 had no follow-up, 2 were hydatid moles, 3 were completed abortions, and 1 was not pregnant. There remained 51 stilbestrol-treated eases ("A" series), and 42 control eases (' 'B'' series). Salvage studies (Table I) reveal that 11 of 51 "A" cases delivered viable infants (21 per cent), and 16 of the 42 "B" cases delivered viable infants (38 per cent). TABLE
I.
COMPARISON OF FINAL RESULTS OF DIETHYLSTILBESTROL-TREATED AND CoNTROL SERIES
SERIES
B
42
16
38
Careful survey of the individual eases suggest that the two series were, so far as could be determined, comparable. In series "A," 3 patients aborted within 24 hours of the beginning of treatment, and, in series "B," 7 aborted
ROBINSON AND
1332
SHJ
.\m. J, Ob,t. & Gynec June, IQ~~
in the same period of time. In series ''A,'' there were 4 cases of fibroids. Three of these patients aborted. In series "B," there were three cases of fihroids. Two of these patients aborted. There were three cases of placenta previa, all occurring in the "B" series. Two of these pregnancies terminated with living infants. No cases of toxemia developed in either series. The salvage rate was higher in both series when bleeding was unaccompanied by cramps (Tables II and III), the salvage rate in series "A" rising to 36 per cent, and in series "B" to 58 per cent. TABLE
II.
TABLB
RESULTS IN PATIENTS HAVING BLEEDING WITHOI'T CRAMPS
ITI.
RESULTS IN PA'fiENTS HAVI:-iG RD;BDINil Wi1'1! CRAMPS ~~~==~=r========~
SERIES
A-(;c;D'C7ie-;-t.--hy"ls-,-til"'b-estrcif)
7
R (Controls)
I
NO. OF CASES
I
---------37-----·~
....
VIABLE INFANTS DELIVERED
PER CENT SALVAGED
7 9
19 30
BO
These results give no evidence of a favorable therapeutic effect from diethylstilbestrol in threatened abortion. Total results, the salvage of 27 of 93 cases, or 29 per cent, do not compare favorably with other reported figures. Hertig and Livingstone, 9 for example, estimated that 20 per cent of all pregnancies threatened to abort with a 50 per cent spontaneous salvage. Parish10 reported a 57 per cent salvage. Colvin and collaborators 11 reported a 70 per cent salvage rate. Rutherford,l 2 however, reported only 24 of 91 threatened abortions carried to term. A possible explanation of our low figure is that all of these were clinic patients who are not likely to report bleeding and cramps as early as the patients seen in private practice.
Comment Various theories have been propounded as to why diethylstilbestrol should be a logical agent in the treatment of threatened abortion. The most widespread theory is that promulgated by the Smiths. 13 They believe that effective action is due to diethylstilbestrol acting like estrogenic oxidation products in causing an increased utilization of chorionic gonadotropin, which, in turn, produces an increased output of progesterone. An adequate production of progesterone is essential for the preservation of pregnancy. Heckel and Allen14 had shown that, in the pregnant rabbit, estrogen administration had maintained progesterone secretion and delayed delivery. The Smiths demonstrated increased pregnandiol excretion following diethylstilbestrol therapy. The Smiths' contention that diethylstilbestrol caused increased progesterone formation as evidenced by increased pregnandiol excretion in the urine has been contested by Davis and Fugo. 16 Hanley 17 was also unable to show increased p1'ogesterone production with diethylstilbestrol treatment in pregnancy. Notwithstanding the questionable modus operandi of diethylstilbestrol in threatened abortion, the high salvage rate in Smith's series (72 per cent) is an excellent attainment, and might be regarded as evidence for the use of diethylstilbestrol on purely empirical grounds. However, Colvin, Bartholomew, Grimes, and Fish 11 reported on 1,570 cases of threatened abortion
Volume 63 Number 6
USE OF DIETHYLSTILBES'rROL IN THREATENED ABORTION
1333
treated conservatively without hormones. Seventy per cent resulted in term babies, 2 per cent in premature deliveries, and 28 per cent aborted. These salvage figures compare favorably with those of Karnaky and Smith. Threatened abortion is not a single disease entity. It is an expression of multiple etiological agents. It is well known that a majority of abortions are due to defective ova. Hertig and Uvingstone, 9 in a study of 1,000 abortions, found 62 per cent were due to abnormal ova. Colvin and associates 11 found 86 per cent of their series aborted because of defective ova. Hertig and Rock 18 have shown that defects in the ovum are apparent even before the first missed menstrual period and thus are not amenable to therapy. The maternal factors in threatened abortion usually listed in the obstetrical textbooks include acute febrile illnesses, surgery, accompanied by sepsis and shock, x-ray therapy, trauma, anesthesia, nutritional deficiencies such as deficiencies of vitamins E. K, and C, endocrine deficiencies such as that of progesterone and thyroid, and anatomical abnormalities. The latter included submucous fibroids, endometrial polyps, previous amputation of the cervix, a septate uterus, and adherent retroversion. Jones and Delfs19 have shown, in studying threatened abortions, that such factors as deficient progesterone production, lowered thyroid .secretion, vitamin E deficiency, uterine abnormalities, and ovular abnormalities may play a role in the abortion. It is obvious that any of these factors might play a role in an individual case of threatened abortion. To expect, on theoretical grounds, that diethylstilbestrol should remedy all these factors appears inconceivable. The present study indicates that diethylstilbestrol is, in fact, a dismal failure in the general treatment of threatened abortion.
Conclusions 1. In a careful comparison of 51 diethylstilbestrol-treated threatened abortions with a control series of 42 untreated cases, there was no evidence that diethylstilbestrol increased the pregnancy salvage rate. 2. On account of the multiplicity of the causes leading to threatened abortion, it is hardly conceivable that one substance could serve as a panacea. 'rhe authors desire to express their grateful appreciation of the helpful suggestions and criticisms given this project by Dr. Howard C. Taylor, Jr.
References 1. 2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Corner, G. W., and Allen, W. M.: Am. J. Physiol. 88: 326, 1929. Reynolds, S. R., and Allen, W. M.: Am. J. Physiol. 102: 3, 1932. Guterman, H. S., and Tulsky, A. G.: AM. J. OBST. & GYNEC. 58: 495, 1949. Karnaky, K. J.: South. M. J. 35: 838, 1942. Smith, 0. W.: AM. J. OBST. & GYNEC. 56: 821, 1948. Karnaky, K. J.: Arizona Med. 8: 36, 1951. (a) Rosenblum, G., and Melinkoff, E.: West. J. Surg. 55: 597, 1947. (b) Ross, J. W.: .J. Nat. M.A. 43: 20, 1951. Crowder, R. E., Bills, E. S., and Broadbent, J. S.: AM. J. OBST. & GYNEC. 60: 896, 1950. Hertig, A. T., and Livingstone, R. C.: New England J. Med. 230: 797, 1944. Parish, T. N.: J. Obst. & Gynaec. Brit. Emp. 42: 1107, 1935. Colvin, E. D., Bartholomew, R. A., Grimes, W. H., and Fish, J.: AM. J. OBST. & GYNEC. 59: 1208, 1950. Rutherford, R.N.: Surg., Gynec. & Obst. 74: 1139, 1942. Smith, 0. W., Smith, G. W., and Schiller, S.: J. Clin. Endocrinol. 1: p. 461, 1941. Heckel, G. P., and Allen, W. M.: Endocrinology 24: 137, 1939. Smith, 0. W., and Smith, G. W.: Proc. Soc. Exper. Bioi. & Med. 57: 198, 1944. Davis, M. E., and Fugo, N. W.: Proc. Soc. Exper. Bioi. & Med. 65: 283, 1947. Hanley, B. J.: Discussion of paper by Colvin, Bartholomew, Grimes, and Fish.n Rock, J., and Hertig, A. T.: AM. J. OBST. & GYNEC. 55: 6, 1948. Jones, G. E. S., and Delfs, E.: J. A.M. A. 146: 1212, 1951.